Nanoparticles, i.e. particles whose diameters are appropriately measured in nanometers, have been considered for a wide variety of end uses. Nanoparticles with appropriate imaging properties are typically based on transition metal oxides, and used as contrast agents for MR and/or X-ray imaging. Iron oxide nanoparticles are used in various therapeutic applications such as iron replacement therapy, magnetic particle imaging (MPI), drug targeting or gene delivery. Preparations containing nanoparticle compositions to be used for in vivo applications in human individuals are typically required to be purified and sterilized to prevent biological contamination, and are often desired to exhibit robust suspension stability in isotonic aqueous media.
Various methods for sterilization of nanoparticles exist, including UV irradiation, ethylene oxide treatment, formaldehyde treatment, sterile filtration, gamma irradiation, and autoclave sterilization. The autoclave sterilization for injectable contrast agents is considered to be one of the most reliable and inexpensive sterilization techniques.
Nanoparticle compositions in aqueous suspension are often subject to agglomeration and precipitation during the use of heat sterilization techniques, such as autoclaving. Efforts have been made to modify the surface properties of such nanoparticles to enhance the stability of aqueous suspensions of such nanoparticles by adding various surface modifiers. Use of a cloud point modifier to alter the temperature at which the nanoparticle aggregation occurs, enabling sterilization via autoclave, is an alternate approach. However, in some cases the cloud point modifiers are charged molecules and are different than the molecules which constitute the shell of the nanoparticles, and that introduces a risk of modifying the surface chemistry of the shell as well as the composition of the nanoparticles.
Methods for stabilizing a nanoparticle composition at elevated temperatures during autoclave sterilization without altering the nanoparticle surface chemistry are highly desirable. A preparation of the nanoparticle composition including improved stability, sterility, enhanced safety, and resistant to aggregation during heat sterilization, is advantageous for various applications.